The spatial and temporal organization of proteins within a cell is critical for coordinating essential activities. Appropriate cellular response to external or internal stimuli often requires precise orchestration by scaffold proteins, which determine the specificity and precise time course of signaling. In particular, the specificity of signal transduction through mitogen activated protein kinase (MAPK) cascades is highly dependent on scaffold proteins. MAPK signaling is involved in the regulation of key cellular behaviors, from proliferation to differentiation and apoptotic death. The overall architecture of three-kinase MAPK cascades is conserved from yeast to mammals. Most cells have multiple MAPKs, MAPK kinases (MAPKKs), and MAPKK kinases (MAPKKKs), so signaling outcome is often determined by scaffolds organizing particular MAPKKK-MAPKK-MAPK complexes.
The c-Jun NH2-terminal protein kinases (JNKs) belong to the MAPK family. JNKs regulate normal physiological processes of cell proliferation, apoptosis, differentiation, and migration. JNKs were also implicated in many diseases, from cancer to neurological and immunological disorders. Full activation of all JNKs requires double phosphorylation of the T-X-Y motif in the activation loop by two upstream kinases, MKK4 (tyrosine) and MKK7 (threonine). Similar to other MAPKs, JNK activation is dependent on scaffolding proteins. Arrestins, which specifically bind active phosphorylated G protein-coupled receptors (GPCRs), were first discovered as negative regulators of GPCR signaling via G proteins. Among the four arrestin subtypes expressed in vertebrates, only arrestin-3 promotes the activation of JNK3, as well as ubiquitous JNK1/2 in cells, acting as a scaffold that brings together MAPKKK ASK1, MAPKKs MKK4 and MKK7, and several isoforms of JNK1/2/3. What is needed are peptides or compounds that can be used to regulate the JNK3 pathway and to treat cellular proliferative disorders.
The compounds, compositions, and methods disclosed herein address these and other needs.